Mechanism of action of the immunosuppressant rapamycin

Rapamycin has potent immunosuppressive properties reflecting its ability to disrupt cytokine signaling that promotes lymphocyte growth and differentiation. In IL-2-stimulated T cells, rapamycin impedes progression through the G1/S transition of the proliferation cycle, resulting in a mid-to-late G1 arrest. Two major biochemical alterations underlie this mode of action. The first one affects the phosphorylation/activation of the p70 S6 kinase (p70(s6k)), an early event of cytokine-induced mitogenic response. By inhibiting this enzyme, whose major substrate is the 4DS ribosomal subunit 56 protein, rapamycin reduces the translation of certain mRNA encoding for ribosomal proteins and elongation factors, thereby decreasing protein synthesis. A second, later effect of rapamycin in IL-2-stimulated T cells is an inhibition of the enzymatic activity ofthe cyclin-dependent kinase cdk2-cyclin E complex, which functions as a crucial regulator of G1/S transition. This inhibition results from a prevention of the decline of the p27 cdk inhibitor, that normally follows IL-2 stimulation. To mediate these biochemical alterations, rapamycin needs to bind to intracellular proteins, termed FKBP, thereby forming a unique effector molecular complex. However, neither p70(s6k) inhibition, nor p27-induced cdk2-cyclin E inhibition are directly caused by the FKBP-rapamycin complex. Instead, this complex physically interacts with a novel protein, designated ''mammalian target of rapamycin'' (mTOR), which has sequence homology with the catalytic domain of phosphatidylinositol kinases and may therefore be itself a kinase. mTOR may act upstream of p70(s6k) and cdk2-cyciin E in a linear or bifurcated pathway of growth regulation. Molecular dissection of this pathway should further unravel cytokine-mediated signaling processes and help devise new immunosuppressants.